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Detail-Document #211113 −This Detail-Document accompanies the related article published in− PHARMACIST’S LETTER / PRESCRIBER’S LETTER
November 2005 ~ Volume 21 ~ Number 211113
Sulfa Drugs and the Sulfa-allergic Patient *Health Canada Product Labeling Listed by Exception* Sulfonamide-Containing Agents: Summary of Cross-Reactivity Information Drug FDA Comments1,2,12 Labeling Recommendations in Sulfonamide Allergy1,2,12 Sulfonylarylamines AntibioticsSulfadiazine,
Contraindications include ophthalmic (sodium sulfacetamide), topical (silver sulfadiazine
[SSD, Silvadene]), and vaginal products (triple sulfa, sulfanilamide) in addition to oral and
Protease InhibitorsAmprenavir (Agenerase) Precaution6
Labeling cautions that the potential for cross-sensitivity with these agents and sulfonamides
is unknown. These agents should be used with caution in patients with a sulfonamide
NonsulfonylarylaminesCarbonic Anhydrase Inhibitors Acetazolamide (Diamox) Contraindicated,
Labeling warns that due to severe reactions to sulfonamides, sensitizations may recur when a
sulfonamide is readministered regardless of route of administration. This warning includes
the ophthalmic preparations (brinzolamide and dorzolamide) because they are absorbed
Two case reports suggest a connection between an anaphylactic reaction with acetazolamide
Copyright 2005 by Therapeutic Research Center
Pharmacist’s Letter / Prescriber’s Letter ~ P.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
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(Detail-Document #211113: Page 2 of 8) Comments1,2,12 Labeling Recommendations in Sulfonamide Allergy1,2,12 Nonsulfonylarylamines (cont.)Cyclooxygenase 2 (COX-2) Inhibitors Celecoxib (Celebrex)
In case reports, celecoxib and valdecoxib have been suggested to cross-react with other
Valdecoxib (Bextra) Contraindicated
sulfonamides. Incidence of allergic reactions to celecoxib was evaluated in three meta-analyses. Combined findings concluded that the risk of cross-reactivity between celecoxib and other sulfonamides is no greater than that seen with placebo or other comparators. Rofecoxib is a sulfone, not a sulfonamide, cross-sensitivity is likely not a concern.
Loop DiureticsBumetanide (Bumex)
Some sources recommend that if a diuretic is used in a patient with a history of sulfonamide
allergy, the first dose should be reduced and given under medical supervision. Referral to an
also listed as warning by allergist may be warranted for patients who have had a severe allergic reaction to a Health Canada)
sulfonamide. Ethacrynic acid does not contain a sulfa group and is a possible alternative in
Torsemide (Demadex) Contraindicated
Bumetanide and furosemide product labeling contain statements that patients may also be
allergic to these drugs if they are allergic to sulfonamides. One case report suggests cross-sensitivity between furosemide and other sulfonamides. Torsemide is contraindicated in patients allergic to sulfonylureas because its chemical structure is a pyridine sulfonylurea. However, none of the product labeling for sulfonylureas contain statements regarding the use of torsemide. One patient that developed angioedema with torsemide treatment was later found to be sulfonamide-allergic.
Copyright 2005 by Therapeutic Research Center
Pharmacist’s Letter / Prescriber’s Letter ~ P.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
www.pharmacistsletter.com ~ www.prescribersletter.com
(Detail-Document #211113: Page 3 of 8) Comments1,2,12 Labeling Recommendations in Sulfonamide Allergy1,2,12 Nonsulfonylarylamines (cont.)SulfonylureasChlorpropamide (Diabinese)
There is one case report of contact dermatitis with tolbutamide in a patient with sensitivity to
sulfanilamide vaginal cream. After discontinuation of tolbutamide, therapy was changed to
chlorpropamide which was tolerated without difficulty. There is also one case report which
describes an allergic reaction to glyburide in a patient with a known allergy to
Micronase)Tolbutamide (Orinase)
(Apo-Tolbutamide – Canada) Tolazamide (Tolinase) None Thiazides and Related CompoundsChlorothiazide (Diuril)
Some sources recommend that if a diuretic is used in a patient with a history of sulfonamide
allergy, the first dose should be reduced and given under medical supervision. Referral to an
allergist may be warranted for patients who have had a severe allergic reaction to a
sulfonamide. Ethacrynic acid does not contain a sulfa group and is a possible alternative in
Case reports suggest cross-reactivity between indapamide and sulfonamide antibiotics.
(Lozide – Canada) Metolazone (Mykrox, Other AgentsProbenecid (Benemid)
(Benuryl – Canada) Sulfasalazine (Azulfidine)
Contraindicated (Also in Sulfasalazine is broken down in the gut into sulfapyridine and 5-aminosalicylic acid
(mesalamine). Sulfasalazine is contraindicated because sulfapyridine is a sulfonylarylamine
Copyright 2005 by Therapeutic Research Center
Pharmacist’s Letter / Prescriber’s Letter ~ P.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
www.pharmacistsletter.com ~ www.prescribersletter.com
(Detail-Document #211113: Page 4 of 8) Comments1,2,12 Labeling Recommendations in Sulfonamide Allergy1,2,12 Nonsulfonylarylamines (cont.)Other Agents (cont.)Tamsulosin (Flomax) Precaution13
Cross-reactivity in sulfa-allergic patient rarely reported. Cautious use recommended with serious or life-threatening sulfa allergy.13
Tipranavir (Aptivus) Precaution10
The potential for cross-sensitivity between drugs in the sulfonamide class and tipranavir (a protease inhibitor) is unknown.10
Sulfonamide Moiety-Containing Drugs5-HT AntagonistsNaratriptan (Amerge)
Sulfonamide group not on benzene ring, FDA concluded no risk of cross-reactivity.
A retrospective chart review evaluated patients with a sulfonamide allergy receiving
sumatriptan. No allergic reactions were reported during sumatriptan therapy.
Other AgentsIbutilide (Corvert) None
(Sotacor – Canada) Topiramate (Topamax)
Zonisamide (Zonegran) Contraindicated11
One small study showed no risk of cross-reactivity when zonisamide was used in patients allergic to sulfonylarylamines.
Users of this document are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and Internet links in this article were current as of the date of publication.
Copyright 2005 by Therapeutic Research Center
Pharmacist’s Letter / Prescriber’s Letter ~ P.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
www.pharmacistsletter.com ~ www.prescribersletter.com
(Detail-Document #211113: Page 5 of 8) Cross-Reactivity of Sulfonamide Drugs Lead authors: Sherri K. Boehringer, Pharm.D., BCPS Background
following initiation of sulfonamide nonantibiotic
An estimated 3% of patients develop allergic
drugs.3 Patients that had previously experienced an
reactions to sulfonamide antibiotics.1 The most
allergic reaction to a sulfonamide antibiotic had a
common type of reaction is a maculopapular rash.
higher occurrence of allergic reactions than did
Rarely, patients develop life-threatening reactions
patients with no history of hypersensitivity to
like anaphylaxis, Stevens-Johnson syndrome, or
sulfonamide antibiotics (9.9% versus 1.6%,
toxic epidermal necrosis. For many years, there has
adjusted odds ratio 2.8; 95% confidence interval,
been debate in the medical community whether all
2.1 to 3.7). However, patients with a prior sulfa
sulfa drugs should be avoided in patients allergic to
allergy were even more likely to have an allergic
reaction to penicillin, obviously a structurally
unrelated drug, than they were to a sulfonamide
How are Sulfa Drugs Classified?
nonantibiotic. Additionally, the risk of an allergic
A sulfonamide is any compound that contains a
reaction after receiving a sulfonamide antibiotic
SO2NH2 moiety.2 Sulfonamides are divided into
was HIGHER in patients with a history of penicillin
three different groups based on chemical structure.
The first group, the sulfonylarylamines, have a
hypersensitivity to sulfonamide antibiotics.
sulfonamide moiety directly attached to a benzene
Some experts also argue that cross-reactivity
ring with an unsubstituted amine (-NH2) moiety at
isn’t possible between the sulfonylarylamines and
the N4 position.2 This group consists primarily of
the other types of sulfonamides because of
the sulfonamide-type antibiotics as well as two
structural differences.2,4 The one structural
protease inhibitors (amprenavir [Agenerase]and
similarity found among the three groups, the
fosamprenavir [Lexiva]). The second group, the
SO2NH2 moiety, hasn’t been shown to interact with
nonsulfonylarylamines, also have a sulfonamide
the immune system.4 However, there are at least
moiety attached to a benzene ring or other cyclic
two known types of allergic reactions related to the
structure, but they do not have an amine group at
sulfonylarylamine structure that require functional
the N4 position. The third group, known as the
groups NOT present in the nonsulfonylarylamines
sulfonamide-moiety containing drugs, have a
sulfonamide group that is not connected to a
The first, type 1 immunological reaction,
benzene ring like in the other groups. The specific
requires the presence of a heterocyclic ring at the
agents included in these three groups are
sulfonamide-N1 position.2,4 This reaction is
immunoglobulin (Ig) E mediated and presents
usually within one to three days after initiation of
The Cross-Reactivity Controversy
medication and is commonly associated with a
Several case reports suggest patients that are
maculopapular eruption or an urticarial rash.2 More
allergic to sulfonamides from one group (e.g.,
sulfonylarylamines) may be at increased risk for
hypotension, and anaphylaxis may also occur,
developing an allergic reaction to a sulfonamide
from another group.2 This is known as cross-
The second, more common hypersensitivity
reactivity. However, there is no data from well
reaction, requires the presence of an unsubstituted
designed trials that show that sulfonamides from
amine group at the N4 position.2,4,5 Cytochrome P-
different groups cross-react. An alternative theory
450 oxidation of the N4 arylamine results in the
to sulfonamide cross-reactivity is that patients
allergic to one drug may be at higher risk for being
hydroxylamine and nitrosoamine metabolites.4,5
allergic to other, even structurally unrelated, drugs.3
This reaction usually develops seven to 14 days
This hypothesis was tested in a retrospective
after initiation of drug therapy and resolves upon
cohort study by Strom et al (n=20,226) that
discontinuation of medication.2 Presentation
evaluated the incidence of allergic reactions
consists of a fever and a nonurticarial rash that may
Copyright 2005 by Therapeutic Research Center
Pharmacist’s Letter / Prescriber’s Letter ~ P.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
www.pharmacistsletter.com ~ www.prescribersletter.com
(Detail-Document #211113: Page 6 of 8)
progress to erythema multiforme and multi-organ
hypersensitivity reactions to trimethoprim-
sulfamethoxazole (Bactrim, Septra). 8
The difference in chemical structure between the
Agents containing sulfur, sulfites, sulfates, and
sulfonylarylamines and other types of sulfonamides
saccharin often confuse clinicians about their
implies that cross-reactivity is unlikely. However,
potential for cross-reactivity with sulfonamides.
T-cell mediated immune response to the Medications that contain sulfur such as amoxicillin unmetabolized, nonhaptenated parent sulfonamide
(Amoxil), captopril (Capoten), omeprazole
antibiotic has been reported to occur occasionally.4
(Prilosec), ranitidine (Zantac), spironolactone
It is unknown whether T-cell recognition is related
(Aldactone), and sulindac (Clinoril) are not
to the sulfonamide moiety or some other functional
sulfonamides and do not cross-react.1 Sulfites
group. Until the mechanism behind T-cell
(sulfur dioxide, sodium sulfite, sodium bisulfite,
recognition is more clearly understood, cross-
potassium bisulfite, sodium metabisulfite, and
reactivity between sulfonylarylamines and the other
potassium metabisulfite) are used in foods and
types of sulfonamides remains theoretically drugs (e.g., Epipen, Pred Forte, Garamycin possible.
injectable, etc.) as antioxidants.1,9 They are also
The protease-inhibitors amprenavir and chemically unrelated to sulfonamides and there is
fosamprenavir are sulfonamides with an N4
no risk of cross-sensitivity. However, sulfites may
arylamine, like the sulfonylarylamine antibiotics.
cause their own reactions such as dyspnea,
The product labeling for these agents state that the
wheeziness, and chest tightness in patients with
potential for cross-sensitivity with other asthma.9 Sulfates (e.g., zinc sulfate, morphine sulfonamides is unknown, but they should be used
sulfate, etc) are also not chemically related to
with caution in people with sulfonamide allergy.6,7
In initial clinical trials, 16 patients with a history of
sulfonamide derivative. This artificial sweetener is
sulfonamide allergy were prescribed amprenavir.2
an ingredient in many liquids and tablets, but is not
Five (31%) of these patients developed a rash which
required to appear in drug labeling.1,9 Dermatologic
resulted in discontinuation of amprenavir in two
reactions and cross-reactivity with sulfonamide
patients. In a clinical study with fosamprenavir
antibiotics have been reported. The American
used as the only protease inhibitor, rash occurred in
Academy of Pediatrics recommends that children
20% of patients with a history of sulfonamide
with sulfonamide allergy avoid saccharin [Evidence
allergy compared to 33% of patients with no history
Other drugs (e.g., some local anesthetics,
Commentary
dapsone, and procainamide) do not contain a
The majority of available evidence suggests that
sulfonamide moiety, but like the sulfonylarylamines
nonsulfonylarylamine and sulfonamide moiety-
contain an N4 arylamine.4 The same is true for
containing drugs need not be routinely avoided in
sunscreens that contain para-amino-benzoic acid
(PABA) derivatives.1 Although, the significance of
this structural similarity is unknown, there have
nonsulfonylarylamines and sulfonamide moieties
been reports of cross-sensitivity between may cause allergic reactions themselves, because of sulfonamides and dapsone, a sulfone.1,8
the stereospecificity of the reaction associated with
Cross-reactivity between dapsone and sulfonylarylamines, cross-reactivity is unlikely.4
sulfonylarylamines appears to be especially The question that remains unanswered is the prevalent in human immunodeficiency virus (HIV)
mechanism behind T-cell recognition, and whether
infected individuals, who are already at a much
it is related to the sulfonamide functional group.4
higher risk of allergic reaction to sulfonamides.1,8
Unfortunately, the product labeling of many
The package labeling of dapsone does not address
nonantibiotic sulfonamide agents does not correlate
the issue of cross-sensitivity with sulfonamides.
with what is known scientifically. For instance,
However, experts state that dapsone may be
many diuretics are either contraindicated or contain
considered in HIV-infected patients with mild
warnings regarding their use in patients with a history of sulfonamide allergy (see table).1,2 The
Copyright 2005 by Therapeutic Research Center
Pharmacist’s Letter / Prescriber’s Letter ~ P.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
www.pharmacistsletter.com ~ www.prescribersletter.com
(Detail-Document #211113: Page 7 of 8)
inconsistency between product labeling and
Level Definition
available evidence is likely because some of these
High-quality randomized controlled trial (RCT)
agents (e.g., hydrochlorothiazide) were marketed
High-quality meta-analysis (quantitative systematic review)
many years before these newer theories refuting
The inconsistency between product labeling and
scientific evidence places clinicians in a difficult
position. The routine avoidance of sulfonamide-
containing drugs in patients with a history of sulfa
compromise patient care. However, to ignore the
product labeling recommendations places clinicians
Adapted from Siwek J, et al. How to write an evidence-based clinical
Patient-specific factors should be considered
review article. Am Fam Physician 2002;65:251-8.
when evaluating the risk of an allergic reaction.1
Allergic reactions may be less common in infants
References
and the elderly, in theory because the immune
1. Which medications to avoid in patients with sulfa
allergy? Pharmacist’s Letter / Prescriber’s Letter
system is immature or senescent. Factors that may
predict drug allergy include a family or personal
2. Johnson KK, Green DL, Rife JP, Limon L.
history of drug allergy, some concurrent illnesses
Sulfonamide cross-reactivity: fact or fiction? Ann
(e.g., HIV), and slow acetylator phenotype.1 One
3. Strom BL, Schinnar R, Apter AJ, et al. Absence of
theory called the “danger hypothesis” suggests that
cross-reactivity between sulfonamide antibiotics and
sulfonamide nonantibiotics. N Engl J Med
predisposition and environmental stress (e.g.,
infection) cause the immune system to become
4. Brackett CC, Singh H, Block JH. Likelihood and
activated resulting in an immune response to
mechanisms of cross-allergenicity between sulfonamide antibiotics and other drugs containing a
sulfonamide functional group. Pharmacotherapy
Ultimately, clinicians will need to make the
decision of whether to initiate sulfonamide drugs in
5. Slatore CG, Tilles SA. Sulfonamide hypersensitivity.
sulfa allergic patients on a case by case basis.
Immunol Allergy Clin North Am 2004;24:477-90.
Prescribing information for Agenerase.
Some experts support using nonsulfonylarylamine
GlaxoSmithKline, Research Triangle Park, NC
and/or sulfonamide moiety-containing medications
in patients allergic to sulfonylarylamines if
alternative therapy with structurally unrelated
Research Triangle Park, NC 27709. July 2005.
compounds is not possible [Evidence level C;
8. Holtzer CD, Flaherty JF Jr, Coleman RL. Cross-
reactivity in HIV-infected patients switched from
expert opinion].2 Exceptions include patients with
trimethoprim-sulfamethoxazole to dapsone.
serious allergic reactions and/or multiple
9. American Academy of Pediatrics. “Inactive“
ingredients in pharmaceutical products: Update
(subject review). 1997 (information current as of
Users of this document are cautioned to use their own professional judgment and consult any other necessary or
http://www.pediatrics.org/cgi/content/full/99/2/268.
appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched
10. Prescribing information for Aptivus. Boehringer
the information with input from experts, government agencies,
Ingelheim Pharmaceuticals, Inc., Ridgefield, CT
and national organizations. Information and Internet links in this article were current as of the date of publication.
11. Prescribing information for Zonegran. Eisai Inc.,
Levels of Evidence
12. Compendium of Pharmaceuticals and Specialties
In accordance with the trend towards Evidence-Based
Medicine, we are citing the LEVEL OF EVIDENCE
www.pharmacists.ca. (Accessed October 19, 2005).
13. Prescribing information for Flomax. Boehringer
Ingelheim Pharm. Ridgefield, CT 06877. Oct. 2005.
Copyright 2005 by Therapeutic Research Center
Pharmacist’s Letter / Prescriber’s Letter ~ P.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
www.pharmacistsletter.com ~ www.prescribersletter.com
(Detail-Document #211113: Page 8 of 8) Cite this Detail-Document as follows: Sulfa drugs and the sulfa-allergic patient. Pharmacist’s Letter/Prescriber’s Letter 2005;21(11):211113.

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